1627902-21-9Relevant academic research and scientific papers
4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate
Letavic, Michael A.,Savall, Brad M.,Allison, Brett D.,Aluisio, Leah,Andres, Jose Ignacio,De Angelis, Meri,Ao, Hong,Beauchamp, Derek A.,Bonaventure, Pascal,Bryant, Stewart,Carruthers, Nicholas I.,Ceusters, Marc,Coe, Kevin J.,Dvorak, Curt A.,Fraser, Ian C.,Gelin, Christine F.,Koudriakova, Tatiana,Liang, Jimmy,Lord, Brian,Lovenberg, Timothy W.,Otieno, Monicah A.,Schoetens, Freddy,Swanson, Devin M.,Wang, Qi,Wickenden, Alan D.,Bhattacharya, Anindya
, p. 4559 - 4572 (2017)
The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
P2X7 MODULATORS
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, (2014/09/29)
The present invention is directed to compounds of Formulas (I, IIa and IIb): The invention also relates to pharmaceutical compositions comprising compounds of Formulas (I, IIa and IIb). Methods of making and using the compounds of Formulas (I, IIa and IIb) are also within the scope of the invention.
